Statistical methods for multivariate meta-analysis of diagnostic tests: An overview and tutorial

In this article, we present an overview and tutorial of statistical methods for meta-analysis of diagnostic tests under two scenarios: 1) when the reference test can be considered a gold standard; and 2) when the reference test cannot be considered a gold standard. In the first scenario, we first review the conventional summary receiver operating characteristics (ROC) approach and a bivariate approach using linear mixed models (BLMM). Both approaches require direct calculations of study-specific sensitivities and specificities. We next discuss the hierarchical summary ROC curve approach for jointly modeling positivity criteria and accuracy parameters, and the bivariate generalized linear mixed models (GLMM) for jointly modeling sensitivities and specificities. We further discuss the trivariate GLMM for jointly modeling prevalence, sensitivities and specificities, which allows us to assess the correlations among the three parameters. These approaches are based on the exact binomial distribution and thus do not require an ad hoc continuity correction. Last, we discuss a latent class random effects model for meta-analysis of diagnostic tests when the reference test itself is imperfect for the second scenario. A number of case studies with detailed annotated SAS code in procedures MIXED and NLMIXED are presented to facilitate the implementation of these approaches

An extended trivariate vine copula mixed model for meta-analysis of diagnostic studies in the presence of non-evaluable outcomes

A recent paper proposed an extended trivariate generalized linear mixed model (TGLMM) for synthesis of diagnostic test accuracy studies in the presence of non-evaluable index test results. Inspired by the aforementioned model we propose an extended trivariate vine copula mixed model that includes the TGLMM as special case, but can also operate on the original scale of sensitivity, specificity, and disease prevalence. The performance of the proposed vine copula mixed model is examined by extensive simulation studies in comparison with the TGLMM. Simulation studies showed that the TGLMM leads to biased meta-analytic estimates of sensitivity, specificity, and prevalence when the univariate random effects are misspecified. The vine copula mixed model gives nearly unbiased estimates of test accuracy indices and disease prevalence. Our general methodology is illustrated by meta-analysing coronary CT angiography studies

CopulaDTA: An R Package for Copula Based Bivariate Beta-Binomial Models for Diagnostic Test Accuracy Studies in a Bayesian Framework

The current statistical procedures implemented in statistical software packages for pooling of diagnostic test accuracy data include hSROC regression and the bivariate random-effects meta-analysis model (BRMA). However, these models do not report the overall mean but rather the mean for a central study with random-effect equal to zero and have difficulties estimating the correlation between sensitivity and specificity when the number of studies in the meta-analysis is small and/or when the between-study variance is relatively large. This tutorial on advanced statistical methods for meta-analysis of diagnostic accuracy studies discusses and demonstrates Bayesian modeling using CopulaDTA package in R to fit different models to obtain the meta-analytic parameter estimates. The focus is on the joint modelling of sensitivity and specificity using copula based bivariate beta distribution. Essentially, we extend the work of Nikoloulopoulos by: i) presenting the Bayesian approach which offers flexibility and ability to perform complex statistical modelling even with small data sets and ii) including covariate information, and iii) providing an easy to use code. The statistical methods are illustrated by re-analysing data of two published meta-analyses. Modelling sensitivity and specificity using the bivariate beta distribution provides marginal as well as study-specific parameter estimates as opposed to using bivariate normal distribution (e.g., in BRMA) which only yields study-specific parameter estimates. Moreover, copula based models offer greater flexibility in modelling different correlation structures in contrast to the normal distribution which allows for only one correlation structure.Comment: 26 pages, 5 figure

Bivariate Random Effects Meta-Analysis of Diagnostic Studies Using Generalized Linear Mixed Models

Bivariate random effect models are currently one of the main methods recommended to synthesize diagnostic test accuracy studies. However, only the logit-transformation on sensitivity and specificity has been previously considered in the literature. In this paper, we consider a bivariate generalized linear mixed model to jointly model the sensitivities and specificities, and discuss the estimation of the summary receiver operating characteristic curve (ROC) and the area under the ROC curve (AUC). As the special cases of this model, we discuss the commonly used logit, probit and complementary log-log transformations. To evaluate the impact of misspecification of the link functions on the estimation, we present two case studies and a set of simulation studies. Our study suggests that point estimation of the median sensitivity and specificity, and AUC is relatively robust to the misspecification of the link functions. However, the misspecification of link functions has a noticeable impact on the standard error estimation and the 95% confidence interval coverage, which emphasizes the importance of choosing an appropriate link function to make statistical inference

Computational Bayesian Methods Applied to Complex Problems in Bio and Astro Statistics

In this dissertation we apply computational Bayesian methods to three distinct problems. In the first chapter, we address the issue of unrealistic covariance matrices used to estimate collision probabilities. We model covariance matrices with a Bayesian Normal-Inverse-Wishart model, which we fit with Gibbs sampling. In the second chapter, we are interested in determining the sample sizes necessary to achieve a particular interval width and establish non-inferiority in the analysis of prevalences using two fallible tests. To this end, we use a third order asymptotic approximation. In the third chapter, we wish to synthesize evidence across multiple domains in measurements taken longitudinally across time, featuring a substantial amount of structurally missing data, and fit the model with Hamiltonian Monte Carlo in a simulation to analyze how estimates of a parameter of interest change across sample sizes

Applying Joint Modelling Regression Approaches in Biomedical Data Science

In recent years, the technological revolution is allowing the collection of an enormous amount of data of different types, creating enormously complex databases that require the collaboration of statisticians and clinicians to carry out a biomedical study with guarantees, applying the tools of data science. This requires the development of new statistical techniques. This thesis focuses on joint modelling regression models for multivariate responses. Specifically, we study the cases of two and three continuous outcomes, as well as models for longitudinal and survival data. These techniques are applied in three studies of major epidemiological importance: liver damage and survival in COVID-19 patients, perinatal mental health during the COVID-19 pandemic, and the study of thyroid-related hormones

Penalized Likelihood Estimation of Trivariate Additive Binary Models

In many empirical situations, modelling simultaneously three or more outcomes as well as their dependence structure can be of considerable relevance. Trivariate modelling is continually gaining in popularity (e.g., Genest et al., 2013; Król et al., 2016; Zhong et al., 2012) because of the appealing property to account for the endogeneity issue and non-random sample selection bias, two issues that commonly arise in empirical studies (e.g., Zhang et al., 2015; Radice et al., 2013; Marra et al., 2017; Bärnighausen et al., 2011). The applied and methodological interest in trivariate modelling motivates the current thesis and the aim is to develop and estimate a generalized trivariate binary regression model, which accounts for several types of covariate effects (such as linear, nonlinear, random and spatial effects), as well as error correlations. In particular, the thesis focuses on the following targets. First, we address the issue in estimating accurately the correlation coefficients, which characterize the dependence of the binary responses conditional on regressors. We found that this is not an unusual occurrence for trivariate binary models and as far as we know such a limitation is neither discussed nor dealt with. Based on this framework, we develop models for dealing with data suffering from endogeneity and/or nonrandom sample selection. Moreover, we propose trivariate Gaussian copula models where the link functions can in principle be derived from any parametric distribution and the parameters describing the association between the responses can be made dependent on several types of covariate effects. All the coefficients of the model are estimated simultaneously within a penalized likelihood framework based on a carefully structured trust region algorithm with integrated automatic multiple smoothing parameter selection. The developments have been incorporated in the function SemiParTRIV()/gjrm() in the R package GJRM (Marra & Radice, 2017). The extensive use of simulated data as well as real datasets illustrates each development in detail and completes the analysis

Multivariate meta-analysis: modelling the heterogeneity mixing apples and oranges; dangerous or delicious?

Meta-analysis may be broadly defined as the quantitative review and synthesis of the results of related but independent studies. For the simple case where meta-analysis concerns only one outcome measure in each study, the statistical methods are well established now. However, in many practical situations there are several outcome measures presented in the individual studies included in a meta- analysis. In that case analyzing each outcome measure separately in a univariate manner is often suboptimal, and analyzing all outcome measures jointly using multivariate methods is indicated. For many situations with multivariate outcome, appropriate meta-analytic method

Copula models for epidemiological research and practice

Investigating associations between random variables (rvs) is one of many topics in the heart of statistical science. Graphical displays show emerging patterns between rvs, and the strength of their association is conventionally quantified via correlation coefficients. When two or more of these rvs are thought of as outcomes, their association is governed by a joint probability distribution function (pdf). When the joint pdf is bivariate normal, scalar correlation coefficients will produce a satisfactory summary of the association, otherwise alternative measures are needed. Local dependence functions, together with their corresponding graphical displays, quantify and show how the strength of the association varies across the span of the data. Additionally, the multivariate distribution function can be explicitly formulated and explored. Copulas model joint distributions of varying shapes by combining the separate (univariate) marginal cumulative distribution functions of each rv under a specified correlation structure. Copula models can be used to analyse complex relationships and incorporate covariates into their parameters. Therefore, they offer increased flexibility in modelling dependence between rvs. Copula models may also be used to construct bivariate analogues of centiles, an application for which few references are available in the literature though it is of particular interest for many paediatric applications. Population centiles are widely used to highlight children or adults who have unusual univariate outcomes. Whilst the methodology for the construction of univariate centiles is well established there has been very little work in the area of bivariate analogues of centiles where two outcomes are jointly considered. Conditional models can increase the efficiency of centile analogues in detection of individuals who require some form of intervention. Such adjustments can be readily incorporated into the modelling of the marginal distributions and of the dependence parameter within the copula model